Melatonin (Structural Formula I) is a hormone that is synthesized in the pineal gland and in the eye and is involved in the regulation of circadian and circannual rhythms. ##STR3## Levels of melatonin are high at night because exposure to light inhibits its synthesis. In addition, melatonin has been shown to lower the body temperature and to have a sedative effect.
Melatonin, and compounds structurally related to melatonin (e.g., substituted indoles), are useful in treating a number of human disorders. For example, sleep disorders, particularly in the elderly, have been shown to respond to treatment with melatonin (Waldhauser, et al, Psychopharmacology, (1990), 100:222; Vollrath, et al Bioscience, (1981), 29:327; Dollins, et al, Proc. Natl. Acad. Sci., (1994), 99:1824). In addition, melatonin has been useful in treating chronobiologic conditions, such as jet lag or work shift changes (Short, et al, U.S. Pat. Nos. 4,600,723 and 4,665,086; Lewy, et al, U.S. Patent No. 5,242,941).
Neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, may also benefit from treatment with melatonin or melatonin derivatives, since levels of melatonin decrease with age (Sack, et al, Pineal Res., (1986), 4:379; Waldhauser, et al, J. Clin. Metab., (1988), 66:645; Van Coevorden, et al, Am. J. Physiolog., (1991), 260:E651). Patients with Alzheimer's disease in particular exhibit circadian rhythm disruptions, and therefore, may benefit from these compounds (Kandel, et al, Principles of Neuroscience, 3rd Edition (1991), Appleton & Lange, Norwalk, Conn., p. 808).
Melatonin has also been shown to have analgesic (Sugden, J. Pharmacol. Exp. Ther., (1983), 227:587) and antiseizure activity (Brailowsky, Electroencephalo. Clin. Neurophysiol., (1976), 41:314; Golombek, et al, Eur. J. Pharmacol., (1992), 210:253). Therefore, compounds related to melatonin may be effective in treating conditions such as migraine headache and epilepsy.
Psychiatric disorders, such as seasonal affective disorder, anxiety disorders, depression, schizophrenia, and mania, may respond to treatment with melatonin related compounds (Dubocovich, U.S. Pat. No. 5,093,352; Miles, et al, Biol. Psychiatry, (1988), 23:405; Sandyk, et al, Schizophr. Bull., (1990), 16:653). For example, manic or depressed patients often exhibit sleep disorders. In addition, melatonin secretion has been shown to be abnormal in humans suffering from anxiety disorder (Mcintyre, et al., Am. J. Psychiat., (1990), 147:462).
Compounds related to melatonin may also be useful in treating precocious puberty, premenstrual syndrome or as fertility or contraceptive agents because production of melatonin is known to change at puberty. In addition, in seasonal breeding species melatonin regulates fertility, hibernation and puberty (Fevre, et al., J. Clin. Endocrinol. Metab., (1978), 47:1383; Parrey, et al., Am. J. Psychiatry, (1987), 144:762; Waldhauser, et al., J. Clin. Endocrinol. Metab., (1991), 73:793; Bispink, et al., J. Pineal Res., (1990), 8:97; Cagnacci, et al., J. Clin. Endocrinol. Metab., (1991), 73:210; Voordouw, et al., J. Clin. Endocrinol. Metab., (1992), 73:107; Fraschini, et al., 5,272,141; Cohen, et al., U.S. Pat. Nos. 4,855,305 and 4,945,103). Therefore, compounds related to melatonin may have applications to animal husbandry.
As described above, abnormalities in melatonin production have been implicated in a number of human and animal disorders. Compounds which are structurally related to melatonin are expected to have many therapeutic applications because they have the potential to mimic the activity of melatonin or block melatonin receptors. A versatile synthetic route that would allow for a variety of substitution patterns would facilitate the production of melatonin related compounds. Melatonin related compounds and their uses are more fully described in U.S. Pat. Nos. 5,403,851 and 5,580,878, the entire teachings of which are hereby incorporated by reference.